Surface layers of Gram-negative bacteria are composed of a cell membrane, a cell wall peptidoglycan, and an outer membrane. The outer membrane contains lipopolysaccharides (hereinafter abbreviated LPS). LPS is a main ingredient of endotoxin which induces endotoxin shock, and consists of an acidic protein component, a high-molecular weight polysaccharide component, and a phospholipid component.
LPS induces various morbid conditions such as pyrogenesis, bleeding, arthritis, and encephalomyelitis. LPS is also known to exhibit a host protection effect on immune-activating mechanisms such as macrophage-activation, B-cell blastogenesis activity, and cell-mediated immunity-activation, as well as antitumour effects such as IFN(interferon) induction and TNF(tumour necrosis factor) induction.
The main component of LPS which exhibits these activities among said three components is the phospholipid component, which is called lipid A. Lipid A comprises a fatty acid residue and phosphoric acid, both of which are combined with a disaccharide amine, and has the following formula [Japanese Bacteriology Journal 40(1), 57(1985) and Proc. Natl. Acad. Sci. U.S.A. 80, 4624(1983)]: ##STR2##
A recent study has revealed that either the non-reducing subunit or the reducing subunit alone as shown above can exhibit the lipid A-like activity, and various analogues have been synthesized based on this finding. Examples of such analogues are disclosed in European Patent Application Disclosure No. 224260, Japanese Patent Application Disclosure No. 62888/90, and Japanese Patent Application Disclosure No. 25494/90, etc.
As described above, extensive studies have been conducted in order to obtain lipid A analogues, specifically by modifying them with various substituents and by changing introduced substituent sites. However, no lipid A analogue has been developed which is pharmaceutically applicable, mainly because the same substituent exhibits different activities depending on its introduced site, thus making the study of pharmaceutical applications of the lipid A-like analogues difficult. Therefore, lipid A analogues of higher activity and lower toxicity are expected to be developed.